MicroRNA profiling identifies a novel compound with antidepressant properties

• Published in: PloS one Vol. 14; no. 8; p. e0221163
• Main Authors: Sell, Stacy L, Boone, Deborah R, Weisz, Harris A, Cardenas, Cesar, Willey, Hannah E, Bolding, Ian J, Micci, Maria-Adelaide, Falduto, Michael T, Torres, Karen E O, DeWitt, Douglas S, Prough, Donald S, Hellmich, Helen L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-08-2019; Public Library of Science (PLoS)
• Subjects: 17β-Estradiol; Anesthesiology; Animals; Antidepressants; Antidepressive Agents - pharmacology; Binding sites; Biology and life sciences; Brain; Brain injuries; Brain Injuries, Traumatic - complications; Brain Injuries, Traumatic - drug therapy; Brain Injuries, Traumatic - genetics; Brain Injuries, Traumatic - pathology; Brain research; Circadian rhythms; Coding; Cognition; Computational Biology; Criminal investigation; Death; Depression (Mood disorder); Depression - complications; Depression - drug therapy; Depression - genetics; Depression - pathology; Disease Models, Animal; Drug therapy; Estradiol; Estradiol - pharmacology; Estrogens; Fluoxetine; Fluoxetine - pharmacology; Gene Expression Regulation - drug effects; Genes; Genetic aspects; Genomes; Genomics; Head injuries; Health care costs; Hippocampus; Hippocampus - drug effects; Hippocampus - pathology; Humans; Hypotheses; Imipramine; Imipramine - pharmacology; Injury analysis; Injury prevention; Medical economics; Medicine and Health Sciences; Mental depression; Mental disorders; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Mood; Neural plasticity; Neurogenesis; Neuroprotection; Neurosciences; Non-coding RNA; Novels; Phenols (Class of compounds); Physiological aspects; Properties (attributes); Psychiatry; Rats; Ribonucleic acid; RNA; Sertraline; Sertraline - pharmacology; Sex hormones; Stem cells; Sulfonamides - pharmacology; Thiazoles - pharmacology; Transcription; Traumatic brain injury; Tricyclic antidepressants; United States; United States > US; Illinois; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0221163

Patients with traumatic brain injury (TBI) are frequently diagnosed with depression. Together, these two leading causes of death and disability significantly contribute to the global burden of healthcare costs. However, there are no drug treatments for TBI and antidepressants are considered off-label for depression in patients with TBI. In molecular profiling studies of rat hippocampus after experimental TBI, we found that TBI altered the expression of a subset of small, non-coding, microRNAs (miRNAs). One known neuroprotective compound (17β-estradiol, E2), and two experimental neuroprotective compounds (JM6 and PMI-006), reversed the effects of TBI on miRNAs. Subsequent in silico analyses revealed that the injury-altered miRNAs were predicted to regulate genes involved in depression. Thus, we hypothesized that drug-induced miRNA profiles can be used to identify compounds with antidepressant properties. To confirm this hypothesis, we examined miRNA expression in hippocampi of injured rats treated with one of three known antidepressants (imipramine, fluoxetine and sertraline). Bioinformatic analyses revealed that TBI, potentially via its effects on multiple regulatory miRNAs, dysregulated transcriptional networks involved in neuroplasticity, neurogenesis, and circadian rhythms- networks known to adversely affect mood, cognition and memory. As did E2, JM6, and PMI-006, all three antidepressants reversed the effects of TBI on multiple injury-altered miRNAs. Furthermore, JM6 reduced TBI-induced inflammation in the hippocampus and depression-like behavior in the forced swim test; these are both properties of classic antidepressant drugs. Our results support the hypothesis that miRNA expression signatures can identify neuroprotective and antidepressant properties of novel compounds and that there is substantial overlap between neuroprotection and antidepressant properties.